Analyte concentration measurement using a hollow frustum

ABSTRACT

A method for measuring the concentration of an analyte in a sample of a biological fluid involves a hollow, frustum-shaped disposable device. The smaller end of the frustum has a porous membrane, to which the sample is applied. Preferably, a reagent in the membrane reacts with the analyte to cause a color change. The device is mounted on a meter, which measures the color change and computes from the change the analyte concentration in the sample. Preferably, the devices are released from the meter without touching them, to protect against contamination.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a meter and disposable device for measuringthe concentration of an analyte in a biological fluid; moreparticularly, an apparatus for which the disposable device is a hollowfrustum.

2. Description of the Related Art

Medical diagnosis often involves measurements on biological fluids, suchas blood, urine, or saliva, that are taken from a patient. Generally, itis important to avoid both contamination of equipment and personnel withthese fluids and to avoid contamination of the patient with fluids fromothers. Thus, there is a need for diagnostic devices that minimize therisk of such contamination.

Among the medical diagnostic devices that are in most widespread usetoday is the blood glucose monitor. In the U.S. alone, there are anestimated 14 million people with diabetes. In order to avoid seriousmedical problems, such as vision loss, circulatory problems, kidneyfailure, etc., many of these people monitor their blood glucose on aregular basis and then take the steps necessary to maintain theirglucose concentration in an acceptable range.

Blood contamination is of concern when making a blood glucosemeasurement. For example, when using the most common types of wholeblood glucose meters (photometric), the glucose determination isgenerally made from a blood sample that is applied to a test strip thatis on the meter. To apply the patient's finger-stick blood sample, thepatient's finger must be positioned above and near to the test strip inorder to inoculate the test strip with the blood sample. There is a riskthat the patient's finger may come into contact with a portion of themeter that is contaminated with blood from previous use by others,particularly when used in a hospital.

This risk to the patient is minimized if the test strip is inoculatedbefore it is placed into the meter. This is the so called "off-meterdosing" approach. With this approach, the patient applies his bloodsample to a reagent test strip as the first step in the measurementprocess. Then the strip is inserted into the meter. The patient's fingeronly comes into contact with a new (clean) disposable, which cannot becontaminated by another patient's blood. The finger never comes intocontact with a contaminated portion of the meter. The approach ofoff-meter dosing has been used for some time, particularly with metersthat operate photometrically, as well as in systems that measurehematocrit. A disadvantage of off-meter dosing is that the meter cannottake a measurement at or before "time-zero", the time when the samplewas applied to the strip. In a photometric meter, a reflectance readingprior to strip inoculation permits the meter to correct for variationsin strip background color and positioning. The meter can also determinetime-zero more directly and more accurately, which facilitates accuratemeasurements. By contrast, time-zero may be difficult or impossible todetermine if the strip is inoculated off-meter.

Although off-meter dosing reduces the contamination problem for thepatient, the meter can still become contaminated with blood. There isthus a risk to others who may come into contact with the contaminatedmeter, such as workers in a hospital and meter repair technicians.Furthermore, if the patient is being assisted by a healthcare worker,that worker could come into contact with the patient's blood whileremoving the strip for disposal, after the test has been completed.

Meters that operate electrochemically typically use "remote dosing", inwhich the test strip is placed in the meter before inoculation, but theblood application point is remote from the meter surfaces that canbecome contaminated. For example, the Glucometer Elite ® from BayerDiagnostics and the Advantage ® from Boehringer Mannheim incorporateelectrodes with remote sample application. As with off-meter dosing,strip removal may also pose a risk for meters that use remote dosing.

A number of systems have been disclosed that are aimed at reducing therisk of contamination to a patient and/or to others in connection withdiagnostic tests.

U.S. Pat. No. 4,952,373, issued Aug. 28, 1990, to Sugarman et al.,discloses a shield that is designed to prevent excess liquid ondiagnostic cartridges from being transferred to a monitor with which thecartridge is used. The shield is fabricated from thin plastic ormetallic film and is attached to a cartridge that is generally the sizeof a credit card.

U.S. Pat. No. 5,100,620, issued Mar. 31, 1992, to Brenneman, disclosesan inverse funnel shaped body with a central capillary tube to transporta liquid sample from a remote sample-application point to a testsurface. The device can be used to transfer blood from a finger stick toa reagent film.

U.S. Pat. No. 3,991,617, issued Nov. 16, 1976, to Marteau d'Autrydiscloses a device that is used with a pipette intended to be used withdisposable tips. The device provides a push button mechanism forejecting the tip from the end of the pipette.

The common element of the above patents is that each of the devicesdisclosed addresses the risk of contamination that is posed bybiological fluids and other potentially hazardous liquids.

SUMMARY OF THE INVENTION

In accordance with the present invention, a device for use in anapparatus for measuring a concentration of an analyte in a sample of abiological fluid comprises

(a) a hollow frustum, having open ends of unequal size and

(b) a porous membrane for accepting the sample, attached to, andsubstantially closing, the smaller open end, the membrane comprising

(i) a surface for accepting the sample and

(ii) a reagent for reacting with the analyte to cause, in a physicallydetectable parameter of the membrane, a change that can be measured andbe related to the concentration of the analyte in the sample.

A method of this invention for measuring a concentration of an analytein a sample of a biological fluid comprises

(a) providing a device that comprises a hollow frustum having open endsof unequal size, whose smaller end is substantially closed by a membranethat has

(i) a surface for accepting the sample and

(ii) a reagent for reacting with the analyte to cause, in a physicallydetectable parameter of the membrane, a change that can be measured andbe related to the concentration of the analyte in the sample;

(b) applying the sample to the membrane surface;

(c) measuring the change in the parameter; and

(d) determining the analyte concentration from the measurement of theparameter change.

The device of the present invention can be used advantageously with ameter for measuring a concentration of an analyte in a sample ofbiological fluid that is applied to a first surface of a porous membranethat contains a reagent, which reacts with the analyte to cause a changein reflectance of a second surface of the membrane, the membrane beingattached to and substantially closing an end of a hollow frustum device.The meter comprises

(a) a body having a frustum-shaped distal section for mating engagementwith the device, the section tapering inwardly to an end that faces thesecond surface of the membrane,

(b) an optical system in the body to direct a beam of light out from thedistal end and to accept light reflected back from the second surface ofthe membrane,

(c) means for measuring the light reflected back into the body bothbefore and after the sample is applied to the membrane, and

(d) means for computing the analyte concentration in the fluid from themeasured values of reflected light.

The device of the present invention permits a person to measure theanalyte concentration in a biological fluid, while minimizing the riskthat the fluid or the user will come into contact with the measurementapparatus. Thus, the device reduces both the likelihood of contaminationof the apparatus by the user and vice versa. The device is disposable,and the terms "device" and "disposable" are used interchangeablythroughout this specification and the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a device of this invention with aportion broken away for clarity;

FIG. 2 is a cross-sectional view taken along line 2--2 of FIG. 1;

FIG. 3 is a perspective view of a meter and device of the inventionprior to their being attached;

FIG. 4 is a perspective view of the meter and device in the process ofobtaining a blood sample;

FIG. 5 is a partial cross-sectional view of the meter and device of FIG.4, taken along line 5--5 of FIG. 4;

FIG. 6 is a side view in partial cross section of a plurality of devicesin a package;

FIG. 7 is a perspective view of a meter of this invention ejecting adevice;

FIG. 8 is a longitudinal cross section, with certain parts in elevationfor clarity, of the meter of FIG. 7 in a first, in-use position;

FIG. 9 is a side elevational view, partially in cross section, of themeter of FIG. 7 in a second, ejection, position;

FIG. 10 is a perspective view of an alternate embodiment of a meter;

FIG. 11 is a perspective view of an alternate embodiment of a device ofthis invention;

FIG. 12 is a fragmentary perspective view of the distal end of thedevice of FIG. 11;

FIG. 13 is a cross-sectional view taken along line 13--13 of FIG. 12;

FIG. 14 is a cross-sectional view taken along line 14--14 of FIG. 12;

FIG. 15 is a cross-sectional view of a further embodiment of the distalend of a device of the invention;

FIG. 16 is a perspective view of another embodiment of a meter anddevice prior to their being attached;

FIG. 17 is another embodiment of a meter and device;

FIG. 18 is a perspective view of the distal end of a further embodimentof the meter and device;

FIG. 19 is a side view of the distal end of the meter and device of FIG.18 shown in an assembled position.

DETAILED DESCRIPTION OF THE INVENTION

The device of the present invention is generally adapted for use in anapparatus for measuring the concentration of analytes, such as alcohol,cholesterol, proteins, ketones, enzymes, phenylalanine, and glucose, inbiological fluids such as blood, urine, and saliva. For brevity, wedescribe the details for using the device in connection withself-monitoring of blood glucose; however, a person of ordinary skill inthe art of medical diagnostics would be able to readily adapt thetechnology for measuring other analytes in other biological fluids.

Self-monitoring of blood glucose is generally done with meters thatoperate on one of two principles. The first is the photometric type,which is based on reagent strips that include a composition that changescolor after blood is applied. The color change is a measure of theglucose concentration.

The second type of blood glucose monitor is electrochemical and operateson the understanding that blood applied to an electrochemical cell cancause an electrical signal--voltage, current, or charge, depending onthe type of meter that can be related to the blood glucoseconcentration.

The present invention permits convenient, remote dosing for bothphotometric and electrochemical systems. For brevity, the descriptionbelow focuses on a photometric system. Similar devices can be used withan electrochemical system. With either type of system, the presentdevice permits the meter to monitor the complete course of the reaction,from the time the sample is applied until a glucose determination ismade. The ability to measure the test start time makes it easier todetermine the glucose concentration accurately.

There are some advantages to using a photometric rather than anelectrochemical system to make a glucose determination. One advantage ofa photometric system is that measurements can be made at more than onewavelength of light, and corrections can be made for variations in bloodhematocrit. The disposable disclosed here provides these advantages ofthe photometric system, while also permitting minimal metercontamination.

The disposables used in photometric measurement systems are generallymade in the form of a thin rectangular strip. The shape derives from theoriginal so-called "dip and read" test strip configuration. One endserves as a handle, while the chemical reaction with the fluid sample iscarried out at the other end.

These rectangular disposables form the male portion of the interfacewith the meter. That is, the strip is retained by features on the meterthat enclose the disposable. This method of retention invitescontamination of the meter with the fluid sample.

In order to avoid the problems of contamination the present disposabletakes the form of a hollow frustum, which provides the female portion ofthe interface with the meter. That is, the disposable encloses a portionof the meter and serves as a cover to prevent contamination of the meterby the fluid sample.

FIG. 1 depicts in partial cutaway an embodiment of this invention inwhich the disposable 10 is a hollow frustum of a cone. Membrane 12 isattached to the smaller end 14. Optional lip 16 provides a surface towhich membrane 12 is attached with adhesive 18. Optional indentations 20are spaced around the circumference of the cone to provide a retentionmechanism, in conjunction with a groove on a meter.

FIG. 2 is a cross section of the disposable of FIG. 1 taken along theline 2--2. As shown in FIG. 2, the membrane is attached to the outsideof the disposable. Alternatively, as shown in FIG. 11, the membrane maybe attached to the inside of the disposable.

FIG. 3 is an exploded perspective view of a photometric meter and adisposable device of the type shown in FIG. 1. Meter 30 has an elongatedconfiguration with a distal section 32 that is a substantiallycylindrically symmetrical frustum, along whose perimeter is optionally agroove 34. Note that the disposable nests on the distal section of themeter in such a way that there is an accurately defined gap G betweenthe distal end 36 of meter 30 and the bottom surface of membrane 12. Theaccurate positioning contributes to measurement precision andreliability. In the cutout can be seen a light source 38 and detector40, which provide for illuminating a disposable and for detecting lightreflected from the disposable, respectively. As discussed below,measuring light reflected from the disposable yields the glucoseconcentration in the sample applied to the membrane. Although only onesource and detector are shown in FIG. 3, multiple sources, optionallyhaving different output spectra, and/or multiple detectors may be used.

FIG. 4 is a perspective view of the way in which a device and meter ofFIG. 3 can be used to obtain a sample S from a stuck finger tip. It isquite easy for the user to bring the disposable into contact with thefinger, which is a big advantage for users that have impaired vision.

FIG. 5 is a cross section of part of distal section 32 of meter 30 anddisposable 10, which illustrates the way indentations 20 and groove 34positively locate meter 30 within disposable 10, leaving gap G. Notethat gap G ensures that blood that penetrates through the membrane doesnot contaminate the meter. The gap dimension, while not critical, ispreferably at least about 1/2 mm.

An advantage of the device of the invention, when used with a meter ofthe type shown in FIG. 3, is that the devices can be in a stack, nestedconveniently in a container 42, as shown in FIG. 6. A device can then besecured simply by inserting the distal section 32 of meter 30 intocontainer 42 and engaging groove 34 and indentations 20. After a testhas been completed, a used disposable can be ejected into wastecontainer W, as shown in FIG. 7, provided there is an optionalpush-button ejection mechanism.

Push-button ejection mechanisms of the type that are widely known andused are suitable for this invention (see e.g.; U.S. Pat. No. 3,991,617.One such mechanism is depicted in FIGS. 8 and 9, which show apush-button mechanism mounted in a meter of the type shown in FIG. 3.The elements of the mechanism include shaft 44, which joins ejector 46and push button 48. Push button 48 works through shaft 44 to causeejector 46 to disengage disposable 10 from the distal section 32 ofmeter 30. Spring 50 works to return the ejector 46 and push button 48 totheir retracted position. Push-button ejection, by permitting thedisposable to be removed without direct contact, helps to avoidcontamination. Disposables to be used with push-button ejectionmechanisms of the type shown in FIGS. 8 and 9 preferably have a flange19.

FIG. 10 depicts an embodiment of a meter of this invention, whichincludes a display 50 for depicting the analyte concentration measuredby the meter. The display can be a light-emitting diode (LED) display, aliquid crystal display (LCD), or similar display well known in the art.

Although the above description and Figs. contemplate a disposable havinga circular cross section and meter having a distal section having amating cross section, that geometry is not essential and, in fact, maynot even be preferred. A primary consideration in selecting the geometryin a photometric system is the optical design. Generally, reflectometrydictates at least a minimum angular separation (typically 45°) between adetector and specularly reflected light. This, in turn requires at leasta minimum vertex angle of the conical disposable. However, it is anadvantage to a user to be able to view his/her finger for dosing, and alarge vertex angle interferes with that view. Thus, a disposable havinga rectangular cross section may be preferred, such as the hollow frustumof a rectangular pyramid 110 shown in FIG. 11. In that case, the angularseparation between detector and specular-reflected light determines onlythe minimum feasible value of L, the longitudinal dimension of thelarger open end. But the disposable could be smaller and provide lessinterference with a user's view of his/her finger. Furthermore,rectangular membranes can be fabricated from ribbons or sheets at lessexpense and with less waste of material. Nevertheless, a circular crosssection is advantageous when an array of several sources and/ordetectors is used in the optical system.

Since contamination is possible if excess sample were to drop from thedisposable, it is desirable to accommodate large samples, withoutdripping. Various designs can serve to retain excess sample. One isshown in FIGS. 12, 13, and 14. FIG. 12 depicts the disposable of FIG. 11with indentations 124 on the small-end surface of the disposable. Asshown in FIGS. 13 and 14, the indentations allow capillary flow to fillthe resulting gap between the membrane and the top inside surface of thedevice. An alternative way of forming such gaps is to adhere themembrane to the disposable with thick adhesive, leaving gaps toaccommodate the excess sample. Another way to absorb excess sample is toattach an absorbent pad 126 over the front surface of the membrane, asshown in FIG. 15.

FIG. 16 is an exploded perspective view of a meter and a disposable ofthe type shown in FIG. 11. The distal section 132 of meter 130 has anoptional groove 134, which is similar to groove 34, for retaining thedisposable. Elongated neck 130 facilitates pickup of disposables fromthe elongated containers 42 shown in FIG. 6. Display 150 depicts themeasured analyte concentration.

FIG. 17 depicts an alternative embodiment of a meter adapted for usewith the disposable of FIG. 11.

FIG. 18 depicts the distal portion of yet another embodiment of adisposable 210 and meter 230. Distal section 232 mates with disposable210. Note that slots 234 are an alternative to groove 34 (or 134) forcapturing indentations, such as 220, on the disposable.

FIG. 19 is a side view of the embodiment of FIG. 18.

In the method of this invention, a blood sample is picked up on theoutward-facing surface of the membrane. Glucose in the sample interactswith a reagent in the membrane to cause a color change, which changesthe reflectance of the inward-facing membrane surface. The light sourcein the meter illuminates the inward-facing membrane surface and measuresthe intensity of light reflected from that surface. Using theappropriate computation, the change in reflectance yields the glucoseconcentration in the sample.

A variety of combinations of membrane and reagent compositions are knownfor photometric determinations of blood glucose concentration. Apreferred membrane/reagent composition is a polyamide matrixincorporating an oxidase enzyme, a peroxidase, and a dye or dye couple.The oxidase enzyme is preferably glucose oxidase. The peroxidase ispreferably horseradish peroxidase. A preferred dye couple is3-methyl-2,2benzothiazolinone hydrazone hydrochloride plus3,3-dimethylaminobenzoic acid. Details of that membrane/reagentcombination and variations on it appear in U.S. Pat. No. 5,304,468,issued Apr. 19, 1994, to Phillips et al., incorporated herein byreference.

Another preferred membrane/reagent composition is an anisotropicpolysulfone membrane (available from Memtec America Corp., Timonium, MD)incorporating glucose oxidase, horseradish peroxidase, and the dyecouple 3-methyl-2-benzothiazolinone hydrazone! N-sulfonylbenzenesulfonate monosodium combined with 8-anilino-1-naphthalenesulfonic acid ammonium. Details of that membrane/reagent combination andvariations on it appear in U.S. patent application Ser. No. 08/302,575,filed Sept. 8,1994, now U.S. Pat. No. 5,563,031 incorporated herein byreference.

It will be understood by those skilled in the art that the foregoingdescriptions of embodiments of this invention are illustrative ofpracticing the present invention but are in no way limiting. Variationsof the detail presented herein may be made without departing from thescope and spirit of the present invention.

I claim:
 1. A method for measuring a concentration of an analyte in asample of a biological fluid comprising(a) providing a device thatcomprises a hollow frustum having open ends of unequal size, whosesmaller end is substantially closed by a membrane that has(ii) a firstoutward facing surface for accepting the sample and (ii) a reagent forreacting with the analyte to cause, in a physically detectable parameterof the membrane, measurable change that is related to the concentrationof the analyte in the sample; (b) applying the sample to the firstsurface; (c) measuring the change in the parameter; and (d) determiningthe analyte concentration from the measurement of the parameter change.2. The method of claim 1 in which the device is provided on an end of anelongated meter, which both supports the device and measures theparameter change.
 3. The method of claim 2 in which the elongated meterhas a frustum-shaped distal section for mating engagement with thedevice for making the measurement.
 4. The method of claim 3 in whichproviding the device on the end of the meter comprises removablyengaging a peripheral groove on the distal section of the meter withindentations on a perimeter of the device, without a user directlycontacting the device.
 5. The method of claim 1 in which the reagentreacts with the analyte to cause a color change, and the membraneparameter whose change is measured is a reflectance of a second, inwardfacing surface, opposite to the first surface.
 6. The method of claim 5in which the sample is whole blood and the analyte is blood glucose. 7.The method of claim 1 further comprising the step of removing the devicefrom the meter, without directly contacting the device.